title: LIF in the regulation of T-cell fate and as a potential therapeutic.
abstract: At the heart of lineage commitment within the adaptive immune response is the intrinsic genetic plasticity of the naive peripheral T lymphocyte (T cell). Primary activation by presentation of cognate antigen is coupled to rapid T-cell cycling and progressive epigenetic changes that guide the cell down distinct T-cell lineages, either effector (Th1, Th2, Th17) or tolerogenic (Treg). Fate choice is influenced both by strength of the priming activation signal and by cues from the micro-environment that are integrated with lineage-specific gene expression profiles, eventually becoming hard-wired in the fully differentiated cell. The micro-environmental cues include cytokines, and the discovery that leukaemia inhibitory factor (LIF) and interleukin (IL)-6 counter-regulate development of the Treg and Th17 lineages places LIF within the core regulatory circuitry of T cells. I first summarise current understanding of LIF and the LIF receptor in the context of T cells. Next, the central relevance of the LIF/IL-6 axis in immune-mediated disease is set in the context of (i) a new nano-therapeutic approach for targeted delivery of LIF and (ii) MARCH-7, a novel E3-ligase discovered to have a central mechanistic role in LIF-mediated T-cell biology, functioning as a rheostat-type regulator of endogenous LIF-signalling.
authors.affiliation: Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. smm1001@cam.ac.uk
authors.forename: S M
authors.initials: SM
authors.lastname: Metcalfe
mesh_terms: D000818:Animals; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D015850:Interleukin-6 / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D009103:Multiple Sclerosis / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology
chemical_list: D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor